Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells

eLife

Irma van de Beek¹  Arjan C Houweling¹  Pino J Poddighe¹  Hanne EJ Meijers-Heijboer²  Martin A Rooimans²  Saskia E van Mil²  Rob MF Wolthuis²  Jesper A Balk²  Iris E Glykofridis²  Puck Veen²  Franziska Böttger³  Connie R Jimenez³  Sinéad M Lougheed³  Jaco C Knol³  Sander R Piersma³  Thang V Pham³  Renee X de Menezes⁴  Jarno Drost⁵  Sepide Derakhshan⁵  Denise Westland⁶  Fried JT Zwartkruis⁶ 

[1] Amsterdam UMC, location VUmc, Vrije Universiteit Amsterdam, Clinical Genetics, Amsterdam, Netherlands;Amsterdam UMC, location VUmc, Vrije Universiteit Amsterdam, Clinical Genetics, Cancer Center Amsterdam, Amsterdam, Netherlands;Amsterdam UMC, location VUmc, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands;NKI-AvL, Biostatistics Unit, Amsterdam, Netherlands;Princess Máxima Center for Pediatric Oncology, Oncode Institute, Heidelberglaan, Utrecht, Netherlands;University Medical Center Utrecht, Center for Molecular Medicine, Molecular Cancer Research, Universiteitsweg, Utrecht, Netherlands;

关键词: renal tumorigenesis;    birt-hogg-dubé syndrome;    FLCN;    TFE3;    STAT2;    mTORC1;   

DOI  :  10.7554/eLife.61630

来源: DOAJ

【 摘 要 】

Germline mutations in the Folliculin (FLCN) tumor suppressor gene cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing carriers to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanism by which FLCN prevents kidney cancer remains unknown. Here, we show that disrupting FLCN in human renal tubular epithelial cells (RPTEC/TERT1) activates TFE3, upregulating expression of its E-box targets, including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, the absence of FLCN or its binding partners FNIP1/FNIP2 induces interferon response genes independently of interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 signaling as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence immune responses. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.

【 授权许可】

Unknown